Abstract Immune tolerance is a multifaceted process, mediated by central and peripheral tolerance, and often resides in a tenuous balance between positive and negative signals. For T cells, central tolerance occurs in the thymus, where negative selection leads to deletion of potentially auto-reactive T cells. On the other hand, peripheral tolerance occurs at many levels, one of which is mediated by a specialized subtype of T cells, the regulatory T cells (Treg). In autoimmune/ auto-inflammatory diseases, this balance is shifted towards T cell activation and effector function versus Treg-mediated T cell suppression. While qualitative or quantitative defects in Treg cells are a possible cause for autoimmune diseases, over the last 10 years increasing evidences from mouse models and human studies suggest that conventional T cells can become refractory to Treg suppression. However, the underlying mechanisms regulating susceptibility to Treg suppression are still poorly understood. Because of the clinical implications, not just for autoimmune diseases but also for anti-tumor immunity, where Treg suppression is still major obstacle, we need additional insights on brakes and accelerators that control T cell responsiveness. Our laboratory has been investigating one of the brakes, the protein tyrosine phosphatase SHP-1, for many years. We have recently identified a new role of SHP-1 in peripheral tolerance. Specifically, T cells lacking SHP-1, display resistance to Treg-mediated suppression both in vitro and in vivo. Here, we hypothesize that loss of SHP1 in conventional T cells causes `qualitative differences' in their functionality that renders them resistant to Treg suppression. Although we are excited about the possible implications of having identified an intracellular signaling molecule that directly affects the responsiveness of a T cell to Treg-mediated suppression, we are now at an intellectual crossroad, necessitating this R21 application. We would like to distinguish - does the resistance of T cells lacking SHP-1 arise from altered early signaling events resulting in a short-term stunting of dampening signals (Aim 1) and/or is this a long-term reprogramming of the T cells in response to SHP-1 deficiency (Aim 2)? To address these possiblitites, we take several unbiased approaches, which are critically needed and form the basis for this application. We believe these studies will be broadly relevant for understanding how conventional non-regulatory T cells respond to Treg-mediated suppression, and will guide us in future research directions.